Current animal models of nicotine addiction may not accurately reflect the biophysical changes that occur in the dopaminergic system and that may be associated with tobacco addiction. This proposal is designed to address a specific concern in regards to studies of tobacco addiction: the effects of multiple smoke constituents on the dopaminergic system (which is primarily involved in tobacco addiction). Current models of tobacco addiction focus solely on chronic nicotine administration and have not included other bioactive components of cigarette smoke, such as monoamine oxidase B (MAO-B) inhibitors, that are potent modulators of dopaminergic function. This is a potentially serious oversight since MAO-B inhibitors are present in significant amounts in cigarette smoke, along with nicotine. The research proposed in this application is designed to examine the effects of chronic nicotine administration in combination with chronic MAO-B inhibition in the mouse brain. Specific aim 1 is designed to study the extent to which chronic exposure to nicotine and an MAO-B inhibitor affects the dopaminergic system in young adult animals (by measuring dopamine & metabolite levels, MAO-B activity, tyrosine hydroxylase protein and mRNA expression, and dopamine transporter expression) and nicotinic acetylcholine receptor(nAChR) expression. Specific aim 2 studies are designed to examine the extent to which changes that occur in the neuronal dopaminergic and nAChR systems effects function of these systems. Thus, specific aim 2 studies will examine the effects of chronic nicotine and MAO-B inhibitor exposure, singly and in combination, on dopamine uptake and nicotine-evoked dopamine release. This proposal is designed to establish a more physiologically accurate model for tobacco addiction. Relevance: The effects of tobacco smoking on public health are well known. Unfortunately, current methods to treat tobacco addiction are not always successful. This project will investigate a model for smoking that may more accurately reflect the changes in the brain seen with tobacco addiction and may provide an improved research model for smoking cessation. [unreadable] [unreadable] [unreadable] [unreadable]